Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Diabetes Care Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
J Biol Chem. 2022 Apr;298(4):101748. doi: 10.1016/j.jbc.2022.101748. Epub 2022 Feb 19.
Adipose tissue dynamically changes its mass in response to external nutritional status, which plays an important role in maintaining the lipid homeostasis. Physiologically, feeding events are associated with the expansion of adipose tissue, but little is known about the detailed molecular mechanisms of this expansion. Here, using comprehensive transcriptome analysis, we found that levels of transforming growth factor β1 (TGF-β1), a key regulator of extracellular matrix (ECM) remodeling, were increased in adipose tissue under feeding conditions and associated with the lipogenic pathway. In addition, TGF-β receptors are highly expressed in adipose tissue, and pharmacological inhibition of TGF-β1 reduced adipose tissue mass and caused ectopic lipid accumulation in the liver. This reduced fat mass was associated with decreased gene expression in ECM remodeling and lipogenesis. Furthermore, similar results were observed in the adipose tissue of SMAD family member 3 knockout mice or upon systemic TGF-β neutralization, with significant reductions in both ECM remodeling and lipogenesis-related genes. Mechanistically, we found that insulin-induced TGF-β1 and cell-autonomous action remodels the ECM of adipocytes, which controls the downstream focal adhesion kinase-AKT signaling cascades and enhances the lipogenic pathway. Of note, destruction of collagens or matrix metalloproteinase/a disintegrin and metalloprotease activities, critical components of ECM remodeling, blocked TGF-β1-mediated focal adhesion kinase-AKT signaling and the lipogenic pathway. Taken together, this study identifies a previously unknown lipogenic role of TGF-β1 by which adipocytes can expand to adapt to physiological feeding events.
脂肪组织会根据外部营养状况动态改变其质量，这对于维持脂质内环境稳定起着重要作用。在生理条件下，进食会导致脂肪组织扩张，但人们对这种扩张的详细分子机制知之甚少。在这里，我们通过综合转录组分析发现，转化生长因子 β1（TGF-β1）水平在进食条件下会增加，而 TGF-β1 是细胞外基质（ECM）重塑的关键调节剂，与脂肪生成途径有关。此外，TGF-β 受体在脂肪组织中高度表达，TGF-β1 的药理学抑制可减少脂肪组织质量并导致肝脏异位脂质积累。这种脂肪量的减少与 ECM 重塑和脂肪生成相关基因的表达下调有关。此外，在 SMAD 家族成员 3 敲除小鼠的脂肪组织或全身性 TGF-β 中和中也观察到了类似的结果，与 ECM 重塑和脂肪生成相关的基因均显著减少。在机制上，我们发现胰岛素诱导的 TGF-β1 和细胞自主作用重塑了脂肪细胞的 ECM，从而控制下游粘着斑激酶-AKT 信号级联，并增强了脂肪生成途径。值得注意的是，胶原或基质金属蛋白酶/解整合素金属蛋白酶的破坏，即 ECM 重塑的关键成分，可阻断 TGF-β1 介导的粘着斑激酶-AKT 信号和脂肪生成途径。总之，这项研究揭示了 TGF-β1 的一个以前未知的脂肪生成作用，脂肪细胞可以通过这种作用来扩张以适应生理进食事件。
